Dataset Information

Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98.

ABSTRACT: The BIG 1-98 trial is a large, randomized, independently conducted clinical trial designed to compare the efficacy of upfront letrozole versus tamoxifen monotherapy and to compare sequential or up-front use of letrozole and/or tamoxifen as an early adjuvant therapy for patients with early breast cancer. We report on the results from the primary core analysis of the BIG 1-98 trial of 8,010 patients, which compares monotherapy with letrozole versus tamoxifen. This pre-planned core analysis allowed the use of patient data from the monotherapy arms of letrozole and tamoxifen and from the sequential arms prior to the drug switch point. Patients randomized to letrozole had a 19% improved disease-free survival (hazard ratio [HR]=0.81; P=0.003), due especially to reduced distant metastases (HR=0.73; P=0.001). A 14% risk reduction of fatal events in favor of letrozole was also observed (P=NS). The results from the monotherapy arms alone confirmed the findings from the primary core analysis. Based on the results from this trial, the aromatase inhibitor letrozole (Femara) is currently recommended as a part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer and has recently been approved in the early adjuvant setting in both Europe and the United States. A subsequent analysis after additional follow-up will address the question of monotherapy versus sequential therapy.

SUBMITTER: Koeberle D

PROVIDER: S-EPMC2001218 | biostudies-other | 2007

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98.

Koeberle Dieter D Thuerlimann Beat B

Breast cancer research and treatment 20071003

The BIG 1-98 trial is a large, randomized, independently conducted clinical trial designed to compare the efficacy of upfront letrozole versus tamoxifen monotherapy and to compare sequential or up-front use of letrozole and/or tamoxifen as an early adjuvant therapy for patients with early breast cancer. We report on the results from the primary core analysis of the BIG 1-98 trial of 8,010 patients, which compares monotherapy with letrozole versus tamoxifen. This pre-planned core analysis allowed ...[more]

PMID: 17912636

Similar Datasets

Project description:BackgroundEarlyR gene signature in estrogen receptor-positive (ER+) breast cancer is computed from the expression values of ESPL1, SPAG5, MKI67, PLK1, and PGR. EarlyR has been validated in multiple cohorts profiled using microarrays. This study sought to verify the prognostic features of EarlyR in a case-cohort sample from BIG 1-98, a randomized clinical trial of ER+ postmenopausal breast cancer patients treated with adjuvant endocrine therapy (letrozole or tamoxifen).MethodsExpression of EarlyR gene signature was estimated by Illumina cDNA-mediated Annealing, Selection, and Ligation assay of RNA from formalin-fixed, paraffin-embedded primary breast cancer tissues in a case-cohort subset of ER+ women (N = 1174; 216 cases of recurrence within 8 years) from BIG 1-98. EarlyR score and prespecified risk strata (≤25 = low, 26-75 = intermediate, >75 = high) were "blindly" computed. Analysis endpoints included distant recurrence-free interval and breast cancer-free interval at 8 years after randomization. Hazard ratios (HRs) and test statistics were estimated with weighted analysis methods.ResultsThe distribution of the EarlyR risk groups was 67% low, 19% intermediate, and 14% high risk in this ER+ cohort. EarlyR was prognostic for distant recurrence-free interval; EarlyR high-risk patients had statistically increased risk of distant recurrence within 8 years (HR = 1.73, 95% confidence interval = 1.14 to 2.64) compared with EarlyR low-risk patients. EarlyR was also prognostic of breast cancer-free interval (HR = 1.74, 95% confidence interval = 1.21 to 2.62).ConclusionsThis study confirmed the prognostic significance of EarlyR using RNA from formalin-fixed, paraffin-embedded tissues from a case-cohort sample of BIG 1-98. EarlyR identifies a set of high-risk patients with relatively poor prognosis who may be considered for additional treatment. Further studies will focus on analyzing the predictive value of EarlyR signature.

Project description:PurposeLuminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years.Patients and methodsBIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported.ResultsOf 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up.ConclusionEfficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.

Project description:ObjectiveOur objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement.EvidenceEach expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence.Consensus processA consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors.ConclusionsThe major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Project description:Title: Transcriptome analysis of human endometrial tissues from healthy post-menoupausal women reflecting the endometrial response to 3-weeks treatment with tibolone, E2 and E2+MPA. In an observational, open, non-randomized, controlled study uterine tissues were collected in order to generate endometrial gene expression profiles. healthy postmenopausal women were enrolled into the following treatment groups: Control-group; Tibolone-group, 2,5 mg of tibolone (administered orally) every day, starting 21 days prior to surgery; Estradiol-group, 2 mg of estradiol (administered orally) every day, starting 21 days prior to surgery; Estradiol+progestagen-group, 2 mg of estradiol (administered orally) and 5 mg of MPA (Medroxy Progesteroneacetate, administered orally) every day, starting 21 days prior to surgery. Pure (100%) endometrium was isolated from the snap-frozen uterine tissues and used for RNA isolation. RNA was labeled and hybridized to whole genome Affymetrix U133plus2 GeneChips containing 54,614 probe sets, representing approximately 47,000 transcripts. Relative to the control group, 940 genes are regulated in the endometrium of E2 treated patients, whereas only 198 genes are significantly regulated in endometria from tibolone or E2+MPA treated patients. Furthermore, only 9% of E2 regulated genes are also regulated by tibolone (85 out of 940), only 5% are also regulated by E2+MPA treatment and the overlap between tibolone and E2+MPA treatment is about 10%. This indicated that tibolone-treatment results in a weak endometrial profile similarity to E2 treatment and no profile similarity to E2+MPA treatment. A more detailed analysis showed that down stream processes, such as regulation of the cell cycle, angiogenesis and cell proliferation are almost not affected by tibolone treatment but, in contrast, are significantly affected by E2. For example, upon staining with Ki67, a marker for mitotic activity, significantly increased stromal as well as glandular cell proliferation was observed in the endometria from the E2-only treated group, while tibolone treatment resulted only in a slight increase in stromal cell proliferation (and no increase in glandular cell proliferation). These results indicate that in contrast to long-term tibolone use, short-term (21-days) use results in some estrogenic stimulation of the endometrium, which is clearly far less and rather different from what is observed during E2 treatment. References: Klaassens et al., 2006 Hanifi-Moghaddam et al., 2007 Verheul et al., 2007

Dataset Information

Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98.

Publications

Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets